We previously identified and molecularly cloned a phosphotyrosine substrate, designated insulin receptor substrate-2 (IRS-2), which possesses over 50 percent homology with IRS-1. While IL-3-dependent 32D cells do not endogenously express IRS molecules, exogenous expression of IRS-1 or IRS-2 restored their capacity to respond mitogenically to IL-4 and insulin. The results suggested that IRS molecules play pivotal role in signal transduction through IL-4 and insulin receptors. In our current study using 32D cell overexpressed IGF-1 receptor, we unexpectedly find that IGF-1 can relay strong proliferative signals in the absence of IRS expression. This result strongly indicates that IGF- 1 receptors can also utilize IRS-independent pathways. Previous attempts to determine if IRS molecules participate in the progression of human cancer have not provided an obvious connection, our current project involving generation of IRS-1 and IRS-2 transgenic mice could potentially unmask a role for these novel docking molecules in neoplasia or other diseases. Recently, we have successfully generated several lines of IRS transgenic mice. Whether IRS overexpression in the transgenic lines affects the onset, severity or pathogenesis of disease will be monitored. - Cell signaling, cytokine, Gene Transcription, immune response, lymphokines, Protein Kinase, receptor signaling, T lymphocytes, - Human Tissues, Fluids, Cells, etc.